Antithrombin III (AT III) prevents LPS-induced pulmonary vascular injury: novel biological activity of AT III.
Acute respiratory distress syndrome (ARDS) adversely affects the outcome of patients with disseminated intravascular coagulation (DIC) associated with sepsis. To determine whether antithrombin III (AT III) is useful for the treatment of ARDS in sepsis, we evaluated the effect of AT III on lipopolysaccharide (LPS)-induced pulmonary vascular injury in rats. Although the intravenous administration of AT III (250 U/kg) prevented LPS-induced pulmonary accumulation of leukocytes, increases in pulmonary vascular permeability, and coagulation abnormalities, inactivated factor Xa, a selective inhibitor of thrombin generation, did not prevent such events other than the coagulation abnormalities. AT III promotes the endothelial release of prostacyclin by interacting with cell surface glycosaminoglycans in vivo. Trp49-modified AT III, which lacks affinity for heparin, did not prevent LPS-induced pulmonary vascular injury. Plasma levels of 6-keto-prostaglandin F1alpha were markedly increased in rats after the administration of LPS and significantly decreased in the LPS-treated rats administered Trp49-modified AT III, but not altered in those LPS-treated rats receiving AT III. Preventive effects of AT III were not observed in rats pretreated with indomethacin, which inhibits prostacyclin biosynthesis. Prostacyclin prevents LPS-induced pulmonary vascular injury by inhibiting leukocyte accumulation in the lungs. These observations strongly suggest that AT III prevents pulmonary vascular injury induced by LPS by promoting the endothelial release of prostacyclin, a potent inhibitor of leukocyte activation.
Uchiba
M
M
Department of Medicine, Kumamoto University School of Medicine, Japan.
Okajima
K
K
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D000990:Antithrombin III / Q000627:therapeutic use*; D001778:Blood Coagulation Disorders / Q000139:chemically induced / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors; D007962:Leukocytes / Q000187:drug effects*; D007970:Leukopenia / Q000139:chemically induced; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D008168:Lung / Q000098:blood supply*; D008297:Male; D008466:Mechlorethamine; D051381:Rats; D017208:Rats, Wistar; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*
D000925:Anticoagulants; D008070:Lipopolysaccharides; D015842:Serine Proteinase Inhibitors; D008466:Mechlorethamine; D015121:6-Ketoprostaglandin F1 alpha; D000990:Antithrombin III; D019272:Leukocyte Elastase